ABSTRACT The Development and Evaluation of Computerized Olfactory Training Program (COT) for Cognitive Decline in Preclinical and Early Alzheimer?s Disease (AD) is a project to develop a home-based brain stimulation device for prevention of AD progression in preclinical and early AD. The success of enriched odor environment for reversal of AD pathology in animals spurred high hopes for translation of olfactory training (OT) into prevention and treatment of AD in humans. OT interventions are based on sniffing from different odorant bottles twice daily for 12-52 weeks, with a once-weekly informal olfactory cognitive component, in which people are asked to subjectively rate how they felt their olfaction had improved. But asking people to subjectively rank their olfactory abilities does not strictly train their olfactory brain structures; and having people sniff from bottles does not take into consideration the fact that olfactory structures differ in their thresholds for activation and desensitization to odor elements. Adaptation of olfactory structures to the odorants limits the extent of neuroplasticity gained from odor enrichment. An alternative strategy is to use a portable, programmed, home-based device to administer olfactory psychophysical tasks while patients are being stimulated repeatedly with a large number of neurotrophic olfactory stimulants, using neuroscience-guided stimulation parameters to ensure sustained activation of all primary and secondary olfactory structures. The small business, Evon Medics and Howard University (HU) have created a prototype called COT (Computerized OT program) to allow automated intensive enrichment of olfactory structures. This proposal will further product development to allow broad COT implementation and commercialization, with customization to prevent progressive cognitive decline in early AD. Project site is the Geriatric clinic at HU. In Aim 1, we will conduct comprehensive functional magnetic resonance imaging (fMRI) evaluation of enrichment molecules and stimulation parameters for maximal activation of the primary and secondary olfactory cortices (POC and SOC). The primary objective is to establish a treatment paradigm of burst frequencies and duration, and interstimulation intervals (ISI) to extensively engage the POC and SOC, taking into consideration differences in patterns of activations and inhibition in these regions. The second objective is to determine brain areas that are differentially activated by psychophysical (e.g. odor identification and memory) tasks, which will serve to optimize brain activities during passive stimulations. The third of objective is to identify a proprietary regimen of the most neuroprotective olfactory stimulants to incorporate into the stimulation and cognitive program. In Aim 2, an optimized COT product will be developed. The current prototype will be improved based on Aim 1 to create a ?test-ready? COT version that includes computerized psychophysical tasks. The psychophysical tasks that activate a region will be paired with stimulation parameters (e.g. burst frequency, duration and ISI) that maximally activate that same region. User-testing of the ?test-ready? COT version will be conducted in patients with mild cognitive impairment (MCI) to gather user feedback and guide further product optimization. In Aim 3 optimized version of the COT will be implemented in MCI and early AD groups to demonstrate pilot effectiveness and cost-effectiveness, compared to usual care and traditional OT. Improvement in olfactory and cognitive functions will be primary outcomes of interest. In addition, a cost analysis will assess the patient and health system costs associated with using COT compared to costs associated with the standard of care and OT. Patient and caregiver satisfaction with COT will be assessed. Project success will be enhanced through strong collaborations between Evon Medics and HU investigators. The investigative team has significant experience in product and business development, AD research, olfactory neuroscience, and development and evaluation of AD interventions. Completion of grant activities will lead to an optimized product to allow COT that overcome the drawbacks of traditional OT in prevention of cognitive decline in AD.